Effects of Bedaquiline Combined with Fluoroquinolone and/or Clofazimine on QT Interval in Patients with Multidrug-Resistant Tuberculosis: a Retrospective Study.

With the application of bedaquiline (Bdq), the success rate of multidrug-resistant tuberculosis (MDR-TB) treatment has been significantly improved; however, the cardiac safety of the patients during treatment cannot be ignored. Hence, this study compared the effects of bedaquiline alone and bedaquiline combined with fluoroquinolones (FQs) and/or clofazimine (CFZ) on the QT interval. This single-center retrospective cohort study analyzed the clinical data of MDR-TB patients treated with bedaquiline for 24 weeks from January 2020 to May 2021 in Xi'an Chest Hospital and compared the changes in QTcF between the two groups. Eighty-five patients were included in the study and grouped by types of anti-TB drugs affecting the QT interval they used. Group A included bedaquiline (n = 33), and group B included bedaquiline in combination with fluoroquinolones and/or clofazimine (n = 52). Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 2.4% (2/85) experienced a postbaseline QTcF of ≥500 ms, and 24.7% (21/85) had at least one change of QTcF of ≥60 ms from baseline. In group A, 9.1% (3/33) had at least one ΔQTcF of >60 ms, as did 34.6% (18/52) of group B. Multivariate Cox regression analysis showed that the adjusted risk of QT prolongation was 4.82 times higher in group B (95% confidence interval [CI], 1.406 to 16.488). Bedaquiline combined with other anti-TB drugs affecting QT interval significantly increased the incidence of grade 3 or 4 QT prolongation; however, no serious ventricular arrhythmia and permanent drug withdrawal occurred. The use of bedaquiline combined with fluoroquinolone and/or clofazimine is an independent risk factor affecting QT interval. IMPORTANCE Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. The emergence of MDR-TB is caused by an organism that is resistant to at least isoniazid and rifampin and is currently considered the major challenge for the global control of TB. Bedaquiline is the first new TB drug in 50 years with a unique mechanism of action, strong anti-M. tuberculosis activity. Yet unexplained excess deaths in the bedaquiline arms have been found in some phase II clinical trials; thus, the FDA has issued a "boxed warning." However, the cardiac safety of the patients during treatment cannot be ignored. Accordingly, further investigations are needed to establish whether bedaquiline combined with clofazimine, fluoroquinolones, or anti-TB drugs affecting the QT interval in a long-course or short-course treatment increases the risk of QT prolongation.

Treatment Outcomes and Risk Factors of Multidrug-Resistant Tuberculosis Patients in Xi'an China, a Retrospective Cohort Study.

Background: Long-term regimens are widely used for multidrug-resistant tuberculosis (MDR-TB) in North-West China; however, risk factors associated with the treatment outcomes are not well known. Methods: This was a retrospective cohort study of MDR-TB patients treated with longer regimen in Xi'an from 2017 to 2019. Risk factors associated with the treatment outcome were analyzed using multiple logistic regression. Results: Of the 446 patients with MDR-TB included, 215 were cured, 84 completed treatment, 23 failed treatment, 108 were lost to follow-up, and 16 died. Unfavorable outcome risk factors were age >40 years (OR = 3.25, 95% CI = 2.12-4.98), male sex (OR = 2.53, 95% CI = 1.52-4.22), and re-treated tuberculosis (OR = 1.70, 95% CI = 1.11-2.61), whereas poor treatment outcome risk factors were age >40 years (OR = 5.51, 95% CI = 2.52-12.07), fluoroquinolones not used in the regimen (OR = 3.31, 95% CI = 1.45-7.51), and smear-positive (OR = 4.0, 95% CI = 1.47-10.8). Conclusion: In Xi'an, MDR-TB treatments with long-term regimens had low success rates, and age, sex, and tuberculosis treatment history were risk factors of MDR-TB treatment outcomes.

Impact of CYP2C19 Genotype and Liver Function on Voriconazole Pharmacokinetics in Renal Transplant Recipients.

BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intraindividual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine. METHODS: A total of 125 trough concentrations (Cmin) from 56 patients were evaluated, retrospectively. Nonlinear mixed effect model was used to describe a PPK model that was internally validated by bootstrap method. Potential covariates included demographic characteristics, physiological and pathological data, concomitant medications, and CYP2C19 genotype. RESULTS: A 1-compartment model with first-order absorption and elimination was fit to characterize the VRC pharmacokinetics in renal transplant recipients (RTRs). Aspartate aminotransferase (AST) had a significant influence on clearance (CL) while CYP2C19 genotype had a major impact on the volume of distribution (V). The parameters of CL and V were 4.76 L/h and 22.47 L, respectively. The final model was V (L) = 22.47 × [1 + 2.21 × (EM = 1)] × [1 + 4.67 × (IM = 1)] × [1 + 3.30 × (PM = 1)] × exp (0.96); CL (L/h) = 4.76 × (AST/33)^(-0.23) × exp (0.14). VRC Cmin in intermediate metabolizers was significantly higher than in extensive metabolizers. CONCLUSIONS: Liver function and CYP2C19 polymorphism are major determinants of VRC pharmacokinetic variability in RTRs. Genotypes and clinical biomarkers can determine the initial scheme. Subsequently, therapeutic drug monitoring can optimize clinical efficacy and minimize toxicity. Hence, this is a feasible way to facilitate personalized medicine in RTRs. In addition, it is the first report about PPK of VRC in RTRs.

Association of keratin 8/18 variants with non-alcoholic fatty liver disease and insulin resistance in Chinese patients: A case-control study.

AIM: To test the hypothesis that K8/K18 variants predispose humans to non-alcoholic fatty liver disease (NAFLD) progression and its metabolic phenotypes. METHODS: We selected a total of 373 unrelated adult subjects from our Physical Examination Department, including 200 unrelated NAFLD patients and 173 controls of both genders and different ages. Diagnoses of NAFLD were established according to ultrasonic signs of fatty liver. All subjects were tested for population characteristics, lipid profile, liver tests, as well as glucose tests. Genomic DNA was obtained from peripheral blood with a DNeasy Tissue Kit. K8/K18 coding regions were analyzed, including 15 exons and exon-intron boundaries. RESULTS: Among 200 NAFLD patients, 10 (5%) heterozygous carriers of keratin variants were identified. There were 5 amino-acid-altering heterozygous variants and 6 non-coding heterozygous variants. One novel amino-acid-altering heterozygous variant (K18 N193S) and three novel non-coding variants were observed (K8 IVS5-9A→G, K8 IVS6+19G→A, K18 T195T). A total of 9 patients had a single variant and 1 patient had compound variants (K18 N193S+K8 IVS3-15C→G). Only one R341H variant was found in the control group (1 of 173, 0.58%). The frequency of keratin variants in NAFLD patients was significantly higher than that in the control group (5% vs 0.58%, P = 0.015). Notably, the keratin variants were significantly associated with insulin resistance (IR) in NAFLD patients (8.86% in NAFLD patients with IR vs 2.5% in NAFLD patients without IR, P = 0.043). CONCLUSION: K8/K18 variants are overrepresented in Chinese NAFLD patients and might accelerate liver fat storage through IR.

Comparison of periarticular anesthesia with liposomal bupivacaine with femoral nerve block for pain control after total knee arthroplasty: A PRISMA-compliant meta-analysis.

BACKGROUND: Periarticular anesthesia (PAI) with liposomal bupivacaine (LB) and femoral nerve block (FNB) were 2 common type of pain management after total knee arthroplasty (TKA). There is no consensus about PAI with LB shows better clinical outcome than FNB. Thus, we performed a systematic review and meta-analysis to compare the efficacy and safety of PAI with LB and FNB for patients prepared for TKA. METHODS: Randomized controlled trials (RCTs) and non-RCTs from PubMed (1966-2017.2), EMBASE (1980-2017.2), and the Cochrane Central Register of Controlled Trials (CENTRAL, 2017.2), Web of Science (1966-2017.2), and Chinese Wanfang database (1980-2017.2) were searched. Continuous outcomes including visual analogue scale (VAS) at 24, 48, and 72 hours, total morphine consumption, length of hospital, and range of motion (ROM) were reported as the weighted mean difference with 95% and confidence interval (CI) and discontinuous outcomes (the occurrence of postoperative nausea and vomiting [PONV]) were presented as relative risk with 95% CI. Random-effects model was adopted to analyze the relevant data. RESULTS: According to the inclusion and exclusion criteria, 8 studies with 2407 patients were eligible and finally included in this meta-analysis (LB = 1114, FNB = 1293). There was no significant difference between VAS at 24, 4, and 72 hours, ROM, and the occurrence of PONV between PAI with LB group versus FNB group (P > 0.05). Compared with the FNB group, PAI with LB was associated with a significant decrease in length of hospital stay by 0.43 day (MD = -0.43; 95% CI -0.60 to -0.27; P = 0.001) and the total dose of total morphine consumption by (MD = -29.32; 95% CI -57.55 to -1.09; P = 0.042). CONCLUSIONS: The review of trials found that PAI with LB provided a significant beneficial effect over FNB in improving the pain or decreased the total morphine consumption in patients who underwent TKA. However, PAI with LB associated with less LOS than FNB. More high quality RCTs are still needed to identify the effects and optimal dose of LB for pain management after TKA.

A sensitive LC-MS/MS method for analysis of pericyazine in presence of 7-hydroxypericyazine and pericyazine sulphoxide in human plasma and its application to a comparative bioequivalence study in Chinese healthy volunteers.

A robust and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of pericyazine in human plasma. The plasma sample was alkalized with sodium hydroxide solution and handled by liquid-liquid extraction with ethyl acetate after adding perphenazine as an internal standard (IS). The analytes were separated on an Ultimate™ AQ-C18 analytical column at 40°C, with a gradient elution consisting of A (aqueous phase: 5mM ammonium acetate buffer solution containing 0.1% formic acid) and B (organic phase: acetonitrile) at a flow rate of 0.350mL/min. The detection was conducted on an API 4000 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) transitions, m/z 366.5>142.4 for pericyazine, m/z 382.5>142.4 for its 7-hydroxy and sulphoxide metabolites and m/z 404.3>171.3 for IS were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity (LLOQ of 0.021ng/mL) and good linearity over the concentration range of 0.021-9.90ng/mL. The intra- and inter-day precision, accuracy, and stability results were within the acceptable limits and no matrix effect was observed. This method was successfully applied in a bioequivalence study to evaluate the pharmacokinetics in 20 healthy male Chinese volunteers. Additional exploratory analyses of 7-hydroxy and sulphoxide metabolites of pericyazine in the same samples suggest that the unchanged drug is predominant in the plasma and suitable for the bioequivalence comparison after a single oral administration of 10mg pericyazine.

Quantitative analysis of valsartan by two-dimensional liquid chromatography (2D-HPLC) and its application in a bioequivalence study in Chinese volunteers
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PURPOSE: To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. METHODS: A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. RESULTS: The calibration range was 9.2 - 4213.8 ng×mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC0→36h and Cmax were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 ± 15.7%. No gender difference was observed in pharmacokinetic parameters. CONCLUSIONS: A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.
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Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Alleviates Doxorubicin-Induced Depressive-Like Behaviors and Neurotoxicity in Rats: Involvement of Oxidative Stress and Neuroinflammation.

Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use can cause neurobiological side-effects associated with depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), the essential fatty acids found in fish oil, possess neuroprotecitve and antidepressant activities. Thus, the aim of this study was to explore the potential protective effects of ω-3 PUFAs against DOX-induced behavioral changes and neurotoxicity. ω-3 PUFAs were given daily by gavage (1.5 g/kg) over three weeks starting seven days before DOX administration (2.5 mg/kg). Open-field test (OFT) and forced swimming test (FST) were conducted to assess exploratory activity and despair behavior, respectively. Our data showed that ω-3 PUFAs supplementation significantly mitigated the behavioral changes induced by DOX. ω-3 PUFAs pretreatment also alleviated the DOX-induced neural apoptosis. Meanwhile, ω-3 PUFAs treatment ameliorated DOX-induced oxidative stress in the prefrontal cortex and hippocampus. Additionally, gene expression of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, and the protein levels of NF-κB and iNOS were significantly increased in brain tissues of DOX-treated group, whereas ω-3 PUFAs supplementation significantly attenuated DOX-induced neuroinflammation. In conclusion, ω-3 PUFAs can effectively protect against DOX-induced depressive-like behaviors, and the mechanisms underlying the neuroprotective effect are potentially associated with its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

Association between Vitamin D Receptor Gene Polymorphisms with Childhood Temporal Lobe Epilepsy.

Vitamin D (VD) is implicated in multiple aspects of human physiology and vitamin D receptor (VDR) polymorphisms are associated with a variety of neuropsychiatric disorders. Although VD deficiency is highly prevalent in epilepsy patients and converging evidence indicates a role for VD in the development of epilepsy, no data is available on the possible relationship between epilepsy and genetic variations of VDR. In this study, 150 controls and 82 patients with temporal lobe epilepsy (TLE) were genotyped for five common VDR polymorphisms (Cdx-2, FokI, BsmI, ApaI and TaqI) by the polymerase chain reaction-ligase detection reaction method. Our results revealed that the frequency of FokI AC genotype was significantly higher in the control group than in the patients (p = 0.003, OR = 0.39, 95% CI = 0.21-0.73), whereas the AA genotype of ApaI SNP was more frequent in patients than in controls (p = 0.018, OR = 2.92, 95% CI = 1.2-7.1). However, no statistically significant association was found between Cdx-2, BsmI and TaqI polymorphisms and epilepsy. Additionally, in haplotype analysis, we found the haplotype GAT (BsmI/ApaI/TaqI) conferred significantly increased risk for developing TLE (p = 0.039, OR = 1.62, 95% CI = 1.02-2.56). As far as we know, these results firstly underline the importance of VDR polymorphisms for the genetic susceptibility to epilepsy.

[Effects of patient-controlled analgesia with small dose ketamine combined with morphine and the influence thereof on plasma beta-endorphin level in patients after radical operation for esophageal carcinoma].

OBJECTIVE: To evaluate the effects of patient-controlled analgesia (PCA) with small dose ketamine combined with morphine on analgesia and influence thereof on the plasma beta-endorphin (EP) level in the patients after radical operation for esophageal carcinoma. METHODS: Thirty ASAI-II patients, aged 35-65, weighing 42-75 kg, with visual analogue score>or=3, undergoing elective radical operation for esophageal carcinoma under general anesthesia received intravenous morphine 2 - 3 mg were randomly divided into 2 equal groups: group m receiving morphine 0.02 mg.kg(-1).h(-1), and with group mk receiving morphine 0.02 mg.kg(-1).h(-1) combined with ketamine 0.08 mg.kg(-1).h(-1) for 50 h. In the course of treatment the patients received intravenous injection of morphine 2-3 mg when the VAS was >or=3. VAS was recorded 4, 8, 20, 24, and 48 h after operation. The amount of morphine used after operation, PCA button pressing times (effective/active), side effects, and vital signs including pulse, saturation of blood oxygen, respiratory rate, heart rate, and average arterial pressure were recorded. Central venous blood samples were collected when entering the operation room (T0), by the end of operation (T1), and 6 h (T2), 24 h (T3), and 48 h (T4) after operation respectively to examine the beta-endorphin level. RESULTS: During the period 4-48 h after operation the VAS scores of the group mk were significantly lower than those of the group m in activity state (all P<0.05) and were not significantly different those of the group m at resting state (all P>0.05). The total amount of morphine consumed and the actual PCA button pressing times were significantly less in the group mk than in the group m (both P<0.05). The incidence rates of nausea, vomiting, and pruritus of the group mk were all significantly lower than those of the group m (all P<0.05). There were not significant differences in the incidence rates of dreaming and pseudoesthesia between these 2 groups. All the vital signs were stable in the 2 groups. The plasma beta-EP levels at the time point T1 of these 2 groups were both significantly higher than those at T0 (both P<0.05). The plasma beta-endorphin levels at T2-4 of the group mk decreased gradually from the level at T1 to the level at T0, and the plasma beta-endorphin levels of the group m rapidly decreased from the level at T0 to the T0 level and remained at this level to the 48 h after operation. CONCLUSION: The combination of small dose of ketamine with morphine provides optimal analgesia with low side-effect rate and little effect on the plasma beta-EP level.